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Category: genetics

Potassium channels functionality is coupled to trafficking!

In a study published recently in PNAS, researchers have revealed the relationship between KCNQ2/3 channel functionality (i.e., how well they work to control electrical signals in neurons) and localization (i.e., where they are found inside a cell), with important implications for the treatment of these epileptic disorders.

For KCNQ2/3 channels to work properly in the brain, they must have full functionality and be located in the correct cellular region – specifically the axon initial segment (AIS), the site in neurons where electric signals are first triggered, controlling nerve cell activity. This led the research team to wonder: does the functionality of KCNQ2/3 channels affect their cellular localization, or are the two not linked at all?

To investigate this potential association, the research team first genetically engineered the functionality of the channels, and then used channel trafficking imaging to visualize whether the channels were taken to their location in the AIS. In this way, they demonstrated that KCNQ2/3 functionality was indeed linked to its trafficking to the correct cellular localization. What’s more, when they used single-molecule imaging, they could see that reduced KCNQ3 functionality actually reduced the AIS localization of KCNQ2/3 by altering the entire trafficking pathway.

“Because we already knew that the localization of KCNQ2/3 to the AIS is regulated by a protein known as ankyrinG, or ankG, we next decided to explore the interactions between full-length KCNQ3 and ankG,” explains lead author of the study. “We found that the active conformation of KCNQ3 was essential for its stable binding to ankG, further confirming that functional KCNQ2/3 is needed to ensure its proper accumulation at the AIS.”

Together, these findings highlight the mechanisms underlying the important link between KCNQ2/3 functionality and localization, and provide clues about how their alterations might affect neuronal excitability. ScienceMission sciencenewshighlights.

Potassium KCNQ2/3 channels are crucial for suppressing the excitability of brain cells, or neurons. When these channels don’t work properly, they can cause specific types of epilepsy like benign familial neonatal convulsions and early infantile epileptic encephalopathy.

Continue reading “Potassium channels functionality is coupled to trafficking!” | >

Insulin Receptor Signaling in Normal and Insulin-Resistant States

In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms.

Light-guided evolution creates proteins that can switch, sense, and compute

Researchers have created a method called optovolution that uses light to guide the evolution of proteins with dynamic behaviors. By engineering yeast cells so their survival depended on proteins switching states at the right time, scientists could rapidly select the best-performing variants. The technique produced new light-sensitive proteins that respond to different colors and improved optogenetic systems. It even evolved a protein that behaves like a tiny logic gate, activating genes only when two signals are present.

Golden lancehead genome reveals how genes responsible for venom toxins evolved

A research team led by scientists at the Butantan Institute in São Paulo, Brazil, has completed the most extensive genetic sequencing of a jararaca viper to date. The focus of the study was the genome of the golden lancehead (Bothrops insularis), particularly its venom genes. Since the species shares most of its genes with the other 48 species in the genus, the data serve as a reference for broader studies on the evolution of jararaca vipers and their toxins. The study is published in the journal Genome Biology and Evolution.

The golden lancehead was described in 1921 as a different species from the one known on the mainland, simply called jararaca (Bothrops jararaca). Isolated on Queimada Grande Island, off the coast of São Paulo, about 100,000 years ago, the population differed from its mainland counterparts to the point of separating into a new species.

In addition to having yellow skin, the golden lancehead is semi-arboreal and feeds on birds as an adult. Jararacas on the mainland, on the other hand, are dark in color and usually hunt small mammals, such as rats, on the ground. In 2021, B. jararaca became the first Brazilian snake to have its genome sequenced.

Scientists discover the switch that revives exhausted cancer-fighting T cells

Scientists have uncovered new genetic rules that determine whether the immune system’s “killer” T cells remain powerful long-term defenders or become worn out and ineffective. By building a detailed genetic atlas of CD8 T cell states, researchers identified key molecular switches that push these cells toward either resilience or exhaustion. Remarkably, disabling just two previously unknown genes restored the tumor-killing power of exhausted T cells while preserving their ability to provide lasting immune protection.

Abstract: In 2015, Philip M

Murphy & colleagues reported on a patient with WHIM syndrome who was cured of the disease by a spontaneous somatic genetic event that deleted the mutant CXCR4 allele in a single hematopoietic stem cell.

Here, the team now show CRISPR silencing of the Cxcr4 overactive disease allele corrects leukopenia in a murine model of WHIM syndrome, demonstrating a new therapeutic strategy for dominant immune disorders.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.

New cellular immunotherapy approach for Alzheimer’s disease

Alzheimer’s disease starts with a sticky protein called amyloid beta that builds up into plaques in the brain, setting off a chain of events that results in brain atrophy and cognitive decline. Microglia, immune cells that reside in the brain, are responsible for removing brain waste but can become dysfunctional when overwhelmed in the context of neurodegenerative disease.

To reduce the cleaning burden on microglia, first author transformed astrocytes, the most abundant cell type in the brain, into amyloid-cleaning machines. The author custom-designed and delivered a gene to astrocytes that codes for the chimeric antigen receptor (CAR) via a harmless virus injected into mice. The CAR, now present on the surface of astrocytes, enabled the cells to capture and engulf amyloid beta proteins. With their newly acquired ability, the astrocytes — generally responsible for keeping the brain tidy — concentrated their efforts on only cleaning amyloid beta plaques in mice prone to its buildup.

Mice carrying genetic mutations that increase people’s risk of developing Alzheimer’s disease develop amyloid beta plaques that saturate the brain by six months of age. The author injected two groups of mice with the virus carrying the CAR-expressing gene: young mice before they developed plaques and older mice with brains saturated with plaques, then, waited three months.

As the younger mice aged, the CAR-astrocytes prevented amyloid beta plaque development. At nearly six months of age, when untreated mice normally have brains saturated with harmful plaques, brains of treated mice were plaque-free. Meanwhile, older mice with plaque-saturated brains at the time of treatment saw a 50% reduction in the amount of amyloid beta plaques compared to mice receiving an injection of a virus lacking the CAR gene.

The researchers have filed a patent related to the approach used to engineer CAR-astrocytes.

“Consistent with the antibody drug treatments, this new CAR-astrocyte immunotherapy is more effective when given in the earlier stages of the disease,” said a co-author on the paper. “But where it differs, and where it could make a difference in clinical care, is in the single injection that successfully reduced the amount of harmful brain proteins in mice.” ScienceMission sciencenewshighlights.

Continue reading “New cellular immunotherapy approach for Alzheimer’s disease” | >

Genetic factors drive the link between cognitive ability and socioeconomic status

A new study of German twins suggests that the strong connection between a young adult’s cognitive ability and their future socioeconomic status is largely driven by their genes, rather than shared family environments or random life events.

Your gut microbes can be anti-aging—scientists are uncovering how to keep your microbiome youthful

People have long given up on the search for the Fountain of Youth, a mythical spring that could reverse aging. But for some scientists, the hunt has not ended—it’s just moved to a different place. These modern-day Ponce de Leóns are investigating whether gut microbes hold the secret to aging well.

The gut microbiome refers to the vast collection of microscopic organisms—bacteria, fungi, and viruses—that largely inhabit the colon. These microbes aid in digestion and produce molecules that affect your physiology and psychology. The composition of the microbiome is influenced by a combination of factors, including genetics, diet, the environment, medications, and age.

I’m a microbiology professor and author of “Pleased to Meet Me: Genes, Germs and the Curious Forces That Make Us Who We Are,” which describes how the gut microbiome contributes to physical and mental health. The discovery that the gut microbiome changes with age has ignited studies to determine whether the Fountain of Youth might be right under your nose, down inside your gut.

DNA barcoding reveals which gene-therapy nanoparticles reach targets in vivo

Drug delivery researchers have vastly improved the potential of genetic therapies by overcoming the challenge of consistently getting genes and gene-editing tools where they need to be within cells. Findings of the study spearheaded by Oregon State University College of Pharmacy graduate student Antony Jozić are published in Nature Biotechnology.

When gene therapies enter a cell, they are often sent to lysosomes, the cell’s trash and recycling centers, where therapeutic genetic material is broken down before it can work. For gene therapies to succeed, they must avoid disposal and reach the part of the cell where they can function.

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